Temporal changes in metabolism guide oligodendrocyte precursor cell dynamics in aging and multiple sclerosis

Neuron

Abstract

Impaired oligodendrocyte precursor cell (OPC) differentiation limits myelin renewal in aging and contributes to multiple sclerosis (MS) progression. How aging drives OPC deficits remains incompletely understood. We find dysregulation of genes associated with the circadian clock, including Bmal1, and metabolism in aged compared with young OPCs. Targeted loss of Bmal1 in OPCs drives metabolic dysfunction, leading to cellular senescence and impaired dynamics. OPC proliferation and differentiation occur at different rates throughout the day in young adult mice and become disrupted with aging. Chronotherapeutic targeting of BMAL1-controlled sirtuin signaling restores Bmal1-disrupted OPC dynamics after demyelination via sirtuin 2 (Sirt2)-dependent mechanisms. Induced pluripotent stem cell (iPSC)-derived OPCs from MS patients and MS lesion oligodendroglia recapitulate BMAL1 and SIRT2 disruptions. These findings establish BMAL1 as a key regulator of OPC energy metabolism, sirtuin homeostasis, and senescence. We anticipate that this work will provide a foundation for future studies investigating the interconnected roles of aging, circadian disruption, and myelin biology.

Authors 17

1. Tess Dierckx

   Stanford Medicine · Stanford University

   Affiliation as printed

   Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA 94305, USA

2. Sarah E. Wilson

   Stanford University

   Affiliation as printed

   Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA 94305, USA; Stem Cell Biology and Regenerative Medicine Graduate Program, Stanford University, Palo Alto, CA 94305, USA

3. Rebecca Buchanan

   Stanford Medicine · Stanford University

   Affiliation as printed

   Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA 94305, USA

4. Themistoklis M. Tsarouchas

   Stanford Medicine · Stanford University

   Affiliation as printed

   Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA 94305, USA

5. Yuhsiang Cheng

   Stanford Medicine · Stanford University

   Affiliation as printed

   Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA 94305, USA; Neurosciences Interdepartmental Graduate Program, Stanford University, Palo Alto, CA 94305, USA

6. Kelly Strickland

   Stanford Medicine · Stanford University

   Affiliation as printed

   Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA 94305, USA

7. Dena Kumsa

   Stanford Medicine · Stanford University

   Affiliation as printed

   Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA 94305, USA

8. Yohan S. S. Auguste

   Stanford Medicine · Stanford University

   Affiliation as printed

   Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA 94305, USA; Neurosciences Interdepartmental Graduate Program, Stanford University, Palo Alto, CA 94305, USA

9. Sam Vanherle

   Hasselt University

   Affiliation as printed

   Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium; University MS Center Hasselt, 3900 Pelt, Belgium

10. Sander Bouwman

    University Medical Center Groningen · University of Groningen

    Affiliation as printed

    Department of Biomedical Sciences, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands

11. Daniela Rojo

    Stanford Medicine · Stanford University

    Affiliation as printed

    Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA 94305, USA

12. Louisa Dal Cengio

    Stanford Medicine · Stanford University

    Affiliation as printed

    Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA 94305, USA

13. Celia Lerma-Martin

    Heidelberg University · Medizinische Fakultät Mannheim

    Affiliation as printed

    Department of Neurology, Division of Neuroimmunology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

14. Yassene Mohammed Aachen Center for Proteomics and Metabolomics

    Leiden University Medical Center

    Affiliation as printed

    Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands

15. Jeroen F. J. Bogie

    Hasselt University

    Affiliation as printed

    Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium; University MS Center Hasselt, 3900 Pelt, Belgium

16. Bart J. L. Eggen

    University Medical Center Groningen · University of Groningen

    Affiliation as printed

    Department of Biomedical Sciences, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; MS Centrum Noord Nederland, Groningen, the Netherlands

17. Erin M. Gibson corresponding

    Stanford Medicine · Stanford University

    Affiliation as printed

    Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA 94305, USA. Electronic address: egibson1@stanford.edu